The present invention relates to cyclopropylindole derivatives and pharmaceutical compositions comprising said derivatives useful for the treatment of various psychiatric disorders and premature ejaculation.
Selective serotonin reuptake inhibitors (SSRIs) are effective for the treatment of mental depression and have been reported to be useful for treating chronic pain. See R. W. Fuller, Pharmacologic Modification of Serotonergic Function: Drugs for the Study and Treatment of Psychiatric and Other Disorders,xe2x80x9d J. Clin. Psychiatry, 47:4 (Suppl.) April 1986, pp. 4-8 and Selective Serotonin Reuptake Inhibitors. Edited by J P Feighner and W F Boyer, Chichester, England. John Wiley and Sons, 1991, pp 89-108. SSRI""s have also demonstrated efficacy for the treatment of anxiety disorders. More recently, SSRI""s have demonstrated efficacy in the treatment of premature ejaculation. See Kim and Paick, Short-term Analysis of the Effects of As Needed Use of Sertraline at 5 pm for the Treatment of Premature Ejaculation, Urology 54:544-547 (1999); Kim and Paick, Self Therapy with Sertraline given PRN at 5 pm in treatment of Premature Ejaculation, Journal of Urology 54:544-547 (1998); McMahon and Touma, Treatment of Premature Ejaculation with Paroxetine Hydrochloride As Needed: 2 Single-Blind Placebo Controlled Crossover Studies Journal of Urology 161:1826-1830 (1999); Haensal et al., Clomipramine and sexual function in men with premature ejaculation and controls Journal of Urology 158:1310-1315 (1998); and McMahon and Touma, Treatment of Premature Ejaculation with Paraoxetine Hydrochloride International Journal Impotence Research 11:241-246 (1999). Thus novel SSRI""s effective for the treatment of these and other disorders would be greatly advantageous.
Thus according to a first embodiment of a first aspect of the present invention are provided compounds of Formula (I) 
and pharmaceutically acceptable salts or solvates thereof
wherein
A1 and A2 are each independently C1-4alkylene or a bond;
A3 is C1-4alkylene or C1-4alkylidene;
A4 is C1-4alkylene or a bond and is attached to X, X1 or X2;
X, X1, X2 and X3 are independently C or CH;
J is C1-4alkyl;
p is 0 or 1;
R1 and R2 are independently H, C1-3alkyl, C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl, xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl or C1-4alkyl-N(H)C(O)Oxe2x80x94;
said C3-6cycloalkyl, phenyl or O-phenyl being independently and optionally substituted with C1-4alkyl, C1-3alkoxy or halo;
or are independently selected from the group of heterocyclic moieties consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano;
or wherein xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl or tetrahydroisoquinolinyl and are optionally substituted with halo, C1-4alkyl, C1-4alkoxy, cyano or benzyl;
R3 is H or C1-4alkyl;
m is 0 or 1;
R4 and R5 are independently hydrogen, cyano, halo, nitro or C1-3perfluoroalkyl;
wherein said R4 or R5 may be independently attached to X, X1, X2 or X3;
n is 0 or 1;
G is N, O or S;
G1 is N or CH;
Y is (D)H wherein D is C; and
Z is (E)H wherein E is C;
provided that
both R4 and R5 are not attached to the same of said X, X1, X2 or X3;
if G is O or S, then m is 0;
if G is N, then m is 1;
if R1 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl, C1-4alkyl-N(H)C(O)Oxe2x80x94 or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A1, then A1 is C2-4alkylene;
if R2 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl, C1-4alkyl-N(H)C(O)Oxe2x80x94 or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A2, then A2 is C2-4alkylene;
if R1 is N(H)C(O)Oxe2x80x94C1-4alkyl, C1-4alkyl-N(H)C(O)Oxe2x80x94 or a heterocyclic moiety selected from the group consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano, then R2 is H or C1-3alkyl;
if R2 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl, C1-4alkyl-N(H)C(O)Oxe2x80x94 or a heterocyclic moiety selected from the group consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano, then R1 is H or C1-3alkyl;
if A4, R4 or R5 are attached to X, then X is C;
if A4, R4 or R5 are attached to X1, then X1 is C;
if A4, R4 or R5 are attached to X2, then X2 is C;
if R4 or R5 are attached to X3, then X3 is C;
if R4 is F and is attached to X and if A3 is methylene, then xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached is not N-methyl-piperazinyl; and
if R4 is F and is attached to X and if A3 is methylene, then xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached is not tetrahydroquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein p is 0.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is N and G1 is CH.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is S and G1 is CH.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is N and G1 is N.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is S and G1 is N.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is O and G1 is N.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is methyl and R2 is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A1 is a bond, R1 is methyl, A2 is a bond and R2 is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R3 is H and m is 1.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 and R5 are halo.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 is hydrogen.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 is fluoro.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 is cyano.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 and R5 are each fluoro.
According to another embodiment of the first aspect of the present invention are compounds of Formula (I) wherein D in relation to the four moieties to which it is attached has an absolute configuration of S; E in relation to the four moieties to which it is attached has an absolute configuration of S; and wherein the hydrogen atom attached to D is in the trans configuration to the hydrogen atom attached to E.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A3 is C1-4alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A3 is C1-4alkylidene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A3 is methylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A4 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A4 is methylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A4 is attached X1.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A4 is attached X.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 is attached X.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A1 is a bond, A2 is a bond, R1 is methyl and R2 is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is independently selected from the group of heterocyclic moieties consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano; A1 is C1-4alkylene; R2 is H or C1-3alkylene; and A2 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is independently selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl; A1 is C1-4alkylene; R2 is H or C1-3alkylene; and A2 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is independently selected from the group of heterocyclic moieties consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano; A2 is C1-4alkylene; R1 is H or C1-3alkylene; and A1 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is independently selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl; A2 is C1-4alkylene; R1 is H or C1-3alkylene; and A1 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are independently H, C1-3alkyl, C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl, or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are independently H, C1-3alkyl, or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are independently H, C1-3alkyl, C3-6cycloalkyl, phenyl, or xe2x80x94O-phenyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are independently H, C1-3alkyl, or are independently selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is H or C1-3alkyl and R1 is C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl, or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is H or C1-3alkyl and R1 is N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is H or C1-3alkyl and R1 is C3-6cycloalkyl, phenyl or xe2x80x94O-phenyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is H or C1-3alkyl and R1 is selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is H or C1-3alkyl and R2 is C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl, or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is H or C1-3alkyl and R2 is N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is H or C1-3alkyl and R2 is C3-6cycloalkyl, phenyl or xe2x80x94O-phenyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is H or C1-3alkyl and R2is selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl and are optionally substituted with benzyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein
A1 and A2 are each independently C1-4alkylene or a bond;
A3 is C1-4alkylene;
A4 is a bond and is attached to X or X1;
R1 and R2 are independently H, C1-3alkyl, C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl;
said C3-6cycloalkyl, phenyl or O-phenyl being independently and optionally substituted with C1-4alkyl, C1-3alkoxy or halo;
or are independently selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl;
or wherein xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl and are optionally substituted with benzyl;
R3 is H or C1-4alkyl;
m is 0 or 1;
R4 is cyano or halo and is attached to X or X1;
n is 0;
X and X1 are each C;
X2 and X3 are each CH;
G is N, O or S;
G1 is N or CH;
Y is (D)H wherein D is C; and
Z is (E)H wherein E is C;
provided that
if G is O or S; then m is 0;
if G is N, then m is 1;
if R1 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A1, then A1 is C2-4alkylene;
if R2 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A2, then A2 is C2-4alkylene;
if R1 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl or said heterocyclic moiety, then R2 is H or C1-3alkyl;
if R2 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl or said heterocyclic moiety, then R1 is H or C1-3alkyl;
if R4 is F and is attached to X and if A3 is methylene, then xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached is not N-methyl-piperazinyl; and
if R4 is F and is attached to X and if A3 is methylene, then xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached is not tetrahydroquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein said compounds exhibit greater SERT binding than hD2L binding as described herein.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein said compounds exhibit less SERT binding than hD2L binding as described herein.
According to various embodiments of a second aspect of the present invention are provided pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein.
The compounds of the present invention may be useful in the treatment or prevention of disorders in which the regulation of monoamide transporter function is implicated. Disease states that may be implicated include hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, paediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache (associated with vascular disorders), emotional lability, pathological crying and sleeping disorder (cataplexy).
Disorders of particular interest include depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders and sexual dysfunction including (in particular) premature ejaculation. The compounds of the present invention may be administered alone or as part of a combination therapy.
Premature ejaculation may be defined as persistent or recurrent ejaculation before, upon or shortly after penile penetration of a sexual partner. It may also be defined as ejaculation occurring before the individual wishes [see The Merck Manual, 16th edition, p. 1576, published by Merck Research Laboratories, 1992].
Thus according to various embodiments of a third aspect of the present invention are provided methods of treating conditions selected from the group consisting of depression, anxiety disorders, premature ejaculation, urinary incontinence, chronic pain, obsessive-compulsive disorder, feeding disorders, premenstrual dysphoric disorder, hot flashes, panic disorders, posttraumatic stress disorder and social phobia comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein.
According to various embodiments of a fourth aspect of the present invention are provided methods of treating psychotic disorders including bipolar disorder and schizophrenia comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) exhibiting greater than or equal hD2L binding than SERT binding as defined herein.
According to various embodiments of a fifth aspect of the present invention are provided methods of enhancing the treatment of conditions selected from the group consisting of depression, anxiety disorders, premature ejaculation, urinary incontinence, chronic pain, obsessive-compulsive disorder, feeding disorders, premenstrual dysphoric disorder, panic disorders, posttraumatic stress disorder and social phobia comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) having SERT binding as defined herein and a pharmaceutically acceptable formulation of agents selected from the group consisting of (Lithium, 5-hydroxytryptophan, or a 5-HT1B/1D antagonist such as (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-morpholino-benzamide.
According to a first embodiment of a sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of a pharmaceutically acceptable formulation comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing a reversible and selective MAO-A inhibitor.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing one or more reversible and selective MAO-A inhibitors selected from the group consisting of moclobemide, brofaromine and befloxatone.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulation comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing a 5-HT1A antagonist.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing a 5-HT1A antagonist selected from the group consisting of pindolol and WAY-100,635.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing a 5-HT1B antagonist.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing a partial 5-HT1A/1B antagonist.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing buspirone.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing methylphenidate.
According to a seventh aspect of the present invention are provided methods of treating obsessive compulsive disorder comprising the administration to an adolescent or child in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing clomipramine.
According to a first embodiment of an eighth aspect of the present invention are provided methods of treating refractory psychotic depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of an antipsychotic agent.
According to another embodiment of the eighth aspect of the present invention are provided methods of treating refractory psychotic depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of an antipsychotic agent selected from the group consisting of aripiprazole, olanzapine, risperdal, clozapine, ziprasidone, haldol, thiothixene and quetiapine fumarate.
According to a ninth aspect of the present invention are provided methods of treating exogenous obesity comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of phentermine.
According to a first embodiment of a tenth aspect of the present invention are provided methods of treating disorders or conditions which can be facilitated by altering circadian rhythms comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of a nitric oxide sythase inhibitor.
According to another embodiment of the tenth aspect of the present invention are provided methods of treating disorders or conditions which can be facilitated by altering circadian rhythms comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of a selective neuronal nitric oxide sythase inhibitor.
According to another embodiment of the tenth aspect of the present invention are provided methods of treating disorders or conditions which can be facilitated by altering circadian rhythms comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of a nitric oxide sythase inhibitor said conditions selected from the group consisting of blindness, obesity, seasonal affective disorder, bipolar disorder, jet lag, circadian sleep rhythms disorder, sleep deprivation, parasomnias, REM sleep disorders, hypersomnia, sleep-wake cycle disorders, narcolepsy and sleep disorders associated with shift work or irregular work schedules, nocturnal enuresis and restless-legs syndrome.
According to another embodiment of the tenth aspect of the present invention are provided methods of treating disorders or conditions which can be facilitated by altering circadian rhythms comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of a selective neuronal nitric oxide sythase inhibitor said conditions selected from the group consisting of blindness, obesity, seasonal affective disorder, bipolar disorder, jet lag, circadian sleep rhythms disorder, sleep deprivation, parasomnias, REM sleep disorders, hypersomnia, sleep-wake cycle disorders, narcolepsy and sleep disorders associated with shift work or irregular work schedules, nocturnal enuresis and restless-legs syndrome.
According to a first embodiment of an eleventh aspect of the present invention is provided a process for the preparation of a compound of Formula (d) 
by reacting a compound of formula (b) 
with a compound of formula (c) 
in the presence of ethyl diazoacetate and toluene, wherein R4 is cyano, halo, nitro or C1-3perfluoroalkyl and X is p-toluenesulfonyl, benzenesulfonyl, methansulfonyl or trifluoromethanesulfonyl.
According to another embodiment of the eleventh aspect of the present invention is provided a process for the preparation of a compound of Formula (d1) 
by reacting a compound of formula (b) 
with a compound of formula (c) 
in the presence of tert-butyl diazoacetate and toluene, wherein R4 is cyano, halo, nitro or C1-3perfluoroalkyl and X is p-toluenesulfonyl, benzenesulfonyl, methansulfonyl or trifluoromethanesulfonyl.
According to a twelvth aspect of the present invention is provided a method of treating sexual dysfunction in a mammal in need thereof comprising the administration of a pharmaceutically acceptable salt or solvate of a compound of Formula (I) and a compound selected from the group of known erectile dysfunction agents including sildenafil.
Other embodiments of the present invention may comprise suitable combinations of two or more of the embodiments and/or aspects disclosed herein.
Yet other embodiments and aspects of the invention will be apparent according to the description provided below.
The description of the invention herein should be construed in congruity with the laws and principals of chemical bonding. For example, it may be necessary to remove a hydrogen atom in order accommodate a substitutent at any given location.
An embodiment or aspect which depends from another embodiment or aspect, will describe only the variables having values or provisos that differ from the embodiment or aspect from which it depends.
If a variable is quantified with a value of zero, then any bond attaching said variable should no longer be represented, e.g., if n in (R3)n equals 0, then the bond attaching R3 to G should no longer be represented.
As used herein, xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo and iodo.
As used herein, xe2x80x9cC1-4alkylenexe2x80x9d means a one to four carbon alkane having one hydrogen atom removed from two different carbon atoms in said alkane, e.g., xe2x80x94CH2CH2CH2xe2x80x94.
As used herein, xe2x80x9cC1-4alkylidenexe2x80x9d means a one to four carbon alkane having two hydrogen atoms removed from one carbon atom in said alkane, e.g., 
It should be understood that the alternating double bond designations in the six-membered ring of the 5,6-membered fused structure represented in Formula (I) are relative and represent the delocalized xcfx80 orbital electrons of said ring.
It is to be understood that the present invention may include any and all possible stereoisomers, geometric isomers, diastereoisomers, enantiomers, anomers and optical isomers, unless a particular description specifies otherwise.
The compounds of this invention may exist in the form of pharmaceutically acceptable salts. Such salts may include addition salts with inorganic acids such as, for example, hydrochloric acid and sulfuric acid, and with organic acids such as, for example, acetic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid and maleic acid. Further, in case the compounds of this invention contain an acidic group, the acidic group may exist in the form of alkali metal salts such as, for example, a potassium salt and a sodium salt; alkaline earth metal salts such as, for example, a magnesium salt and a calcium salt; and salts with organic bases such as a triethylammonium salt and an arginine salt. In the case of a sublingual formulation a saccharin salt or maleate salt may be of particular benefit. The compounds of the present invention may be hydrated or non-hydrated.
The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of this invention may also be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those skilled in the pharmaceutical arts. The compounds can be administered alone, but generally will be administered with a pharmaceutical carrier selected upon the basis of the chosen route of administration and standard pharmaceutical practice. Compounds of this invention can also be administered in intranasal form by topical use of suitable intranasal vehicles, or by transdermal routes, using transdermal skin patches. When compounds of this invention are administered transdermally the dosage will be continuous throughout the dosage regimen.
The dosage and dosage regimen and scheduling of a compounds of the present invention must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and extent of the disease condition. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level which will produce effective beneficial effects without causing any harmful or untoward side effects.
Compounds of the present invention may be synthesized according to the general schema provided below. Variables provided in the schema below are defined in accordance with the description of compounds of the above Formulae unless otherwise specified.
A preferred method for the preparation of trans-cyclopropanes of Formula I is illustrated in Scheme 1. A appropriately substituted heterocyclic aldehyde, where Pg is a protecting group such as p-toluenesulfonyl when G is nitrogen, is reacted with a appropriated olefinating reagent, such as a Homer-Emmons reagent. The resulting heterocyclic trans-acrylic acid derivative, preferably the N-methoxy-N-methyl amide, is cyclopropanated using reagents such as diazomethane and palladium(II)acetate, or trimethylsulfoxonium iodide with an appropriate base. The resulting cyclopropyl amide derivative is reduced to the aldehyde using reagents such as LAH, or the like. Subsequent reductive amination using an appropriately substituted amine with an reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or the like, gives the cyclopropyl methyl amine. Removal of protecting groups, such as the p-toluenesulfonyl group, when G is nitrogen, using mild basic hydrolysis, gives the trans-cyclopropyl compounds of Formula 1. 
A preferred method of preparing cis-cyclopropyl compounds of Formula I is described in Scheme 2. This method is similar to that in Scheme 1, except for the use of olefinating reagents, such as the trifluoroethyl Horner-Emmons reagent, that selectively give the heterocyclic cis-acrylic acid derivatives, where Pg is a protecting group such as p-toluenesulfonyl when G is nitrogen. Further reaction of the cis-acrylic acid derivatives, in a manner similar to that described in Scheme 1, provides the cis-cyclopropyl compounds of Formula I. 
A preferred method for the preparation of compounds of Formula I where A3 is a branched alkylidene chain is illustrated in Scheme 3. The N-methoxy-N-methyl-cyclopropyl carboxamide intermediate, where Pg is a protecting group such as p-toluenesulfonyl when G is nitrogen, is reacted with a nucleophile, such as a alkyl magnesium halide or alkyl lithium. The resulting cyclopropyl alkyl ketone is reductively aminated and subsequently deprotected in a manner similar to that described in Scheme 1 to give compounds of Formula I where A3 is a branched alkylidene chain. 
Another preferred method for the preparation of compounds of Formula I is illustrated in Scheme 4. An appropriately substituted vinyl heterocycle, where Pg is a protecting group such as p-toluenesulfonyl when G is nitrogen, is reacted with an appropriate diazoacetate ester, such as ethyl or tert-butyl diazoacetate, in the presence of a catalyst such as the Nishiyama catalyst. [(R)-trans-Cl2Ru(pybox-ip)(CH2xe2x95x90CH2) was prepared from 2,6-bis(4R)-(+)-isopropyl-2-oxazolin-2-yl]pyridine (Aldrich Chemical Co.) according to: Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am. Chem Soc. 1994, 116, 2223.] The resulting cyclopropyl ester is reduced to the alcohol using reagents such as DIBAL, LAH, or the like. The resulting alcohol is then oxidized to the corresponding aldehyde using standard methods, such as PCC or DMSO/oxalyl chloride. The resulting aldehyde is then converted to the compounds of Formula 1 by the methods outlined in Scheme 1. 
The vinyl heterocycle intermediates, where Pg is a protecting group such as p-toluenesulfonyl when G is nitrogen, can be prepared in several ways (Scheme 5). Treatment of an appropriate aldehyde with an organometalic reagent such a methyl magnesium bromide, or the like, with subsequent dehydration of the resulting alcohol using reagents such as p-toluene sulfonic acid, or the like, is one preferred method for the preparation of the vinyl heterocycle intermediates. Another preferred method consists of acetylation of the heterocycle using reagents such as acetyl chloride and diethylaluminum chloride, or the like, followed by the optional protection of the heterocycle using p-toluenesulfonyl chloride and triethyl amine, or the like. Reduction of the acetyl group using sodium borohydide, or the like, with subsequent dehydration of the resulting alcohol gives the vinyl heterocycle. 
The preparation of indazole compounds of Formula 1 is described in Scheme 6. The aryl cyclopropyl ketone intermediate is prepared my methods known to those skilled in the art, such as a palladium mediated coupling of an aryl boronate with a cyclopropane thioester. This ketone intermediate is reacted with an appropriately substituted hydrazine, such as p-toluenesulfonylhydrazide, and subsequently cyclized to an indazole under mild basic conditions, such as potassium carbonate. The resulting cyclopropyl ester is converted to compounds of Formula 1 by methods similar to those described in Scheme 3. 
The preparation of compounds of Formula 1, where G is sulfur, is described in Scheme 7. The appropriately substituted carboxaldehyde is carried through a reaction sequence in a manner similar to that described in Scheme 1 to give the compounds of Formula I, where G is sulfur. 
The preparation of indole and indazole compounds of Formula 1, where R3 is lower alkyl, is described in Scheme 8, along with the preparation quaternary alkyl ammonium salts of compounds of Formula 1. Indole and indazole compounds of Formula 1, where R3 is H, are reacted with bases such as sodium hydride or potassium tert-butoxide in the presence of alkylating reagents, such as dimethyl sulfateor diethyl sulfate, to give derivatives where where R3 is lower alkyl. Quaternary alkyl ammonium salts of compounds of Formula 1, are prepared by reaction of tertiary amine compounds of Formula 1 with alkyl halides, such as methyl iodide. 
Another preferred method for preparing compounds of Formula 1, where A4 is attached at points X, X1, or X2, is described in Scheme 9. An appropriately substituted heterocycle, with a reacting group Rg (such as iodo, bromo, or trifluoromethanesulfonyl groups) is present at points X or X2 is reacted with an appropriately substituted acryamide under catalysis with palladium(II)acetate, or the like. The resulting substituted acrylamide derivative is converted to compounds of Formula I by methods similar to those described in Scheme 1. The substituted acrylamide derivative can also be prepared from appropriately substituted heterocyclic aldehyde, where the aldehyde is attached at points X, X1, or X2. Olefination of the aldehyde with the Horner-Emmons reagent under conditions described in Scheme 1 also gives the substituted acrylamide derivative which can be converted to compounds of Formula I by methods similar to those described in Scheme 1. 
Other suitable means of synthesizing said compounds may also be available. More detailed descriptions of synthesizing compounds of the present invention are also provided. The required starting materials and reagents, such as substituted indoles and indolecarboxaldehydes, for these methods can be obtained from commercial sources. Other starting materials that are not commercially available can be prepared by standard methods known to those skilled in the art.